WO2017136708A1 - Synthesis and composition of rapafucin libraries - Google Patents

Synthesis and composition of rapafucin libraries Download PDF

Info

Publication number
WO2017136708A1
WO2017136708A1 PCT/US2017/016481 US2017016481W WO2017136708A1 WO 2017136708 A1 WO2017136708 A1 WO 2017136708A1 US 2017016481 W US2017016481 W US 2017016481W WO 2017136708 A1 WO2017136708 A1 WO 2017136708A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
alkenyl
alkynyl
Prior art date
Application number
PCT/US2017/016481
Other languages
French (fr)
Inventor
Jun Liu
Jingxin Wang
Zufeng Guo
Sam Hong
Wukun LIU
Hanjing Peng
Manisha Das
Original Assignee
The Johns Hopkins University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Johns Hopkins University filed Critical The Johns Hopkins University
Priority to CA3013589A priority Critical patent/CA3013589A1/en
Priority to EP17748264.3A priority patent/EP3411413A4/en
Priority to CN201780010182.2A priority patent/CN108713028B/en
Priority to JP2018540102A priority patent/JP6891183B2/en
Priority to MX2018009405A priority patent/MX2018009405A/en
Priority to AU2017214550A priority patent/AU2017214550B2/en
Priority to US16/074,017 priority patent/US10662220B2/en
Publication of WO2017136708A1 publication Critical patent/WO2017136708A1/en
Priority to US16/590,087 priority patent/US11066416B2/en
Priority to US17/332,331 priority patent/US11945827B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C07K17/02—Peptides being immobilised on, or in, an organic carrier
    • C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2570/00—Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the invention relates generally to hybrid cyclic molecules, and more specifically to hybrid cyclic libraries based on the immunophilin ligand family of natural products FK506 and rapamycyin.
  • FK506 and rapamycin are approved immunosuppressive drugs with important biological activities. Both have been shown to inhibit T cell activation, albeit with distinct mechanisms.
  • rapamycin has been shown to have strong anti-proliferative activity.
  • FK506 and rapamycin share an extraordinary mode of action; they act by recruiting an abundant and ubiquitously expressed cellular protein, the prolyl cis-trans isomerase FKBP, and the binary complexes subsequently bind to and allosterically inhibit their target proteins calcineurin and mTOR, respectively. Structurally, FK506 and rapamycin share a similar FKBP-binding domain but differ in their effector domains.
  • One embodiment of the present invention is to provide a compound of the following structure:
  • R 1 and R 3 can independently be any of the following compounds:
  • R 2 and R 4 can independently be any of the following compounds:
  • Another embodiment of the present invention is to provide a compound of the following structure:
  • R 1 , R 2 , R 3 and R 4 are selected from the same groupings of compounds listed above.
  • Another embodiment of the present invention is to provide a compound that includes A15-34-2, A15-39-1, A15-39-2, A15-39-4, A15-39-6, A15-39-8, A15-39-15, A15- 40-2, A15-40-4, A15-40-15, E15-32-2, E15-33-1, E15-33-2, E15-34-1, E15-34-2, E15-39-1, E15-39-2, E15-39-5, E15-40-2, E15-40-4, E15-S-19, E15-S-21, and E15-S-22.
  • Another embodiment of the present invention is to provide synthetic methods as outlined in the“Detailed Description of the Invention” for producing a Rapafucin library.
  • Figure 1 Number of compounds in library. DETAILED DESCRIPTION OF THE INVENTION
  • R 1 and R 3 in Scheme 1 are amino acids selected from the following group of amino acids:
  • R 2 and R 4 in Scheme 1 are amino acids selected from the following group of amino acids:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A Rapafucin library containing compounds of the general structure, (A) and (E), and a synthesis of these compounds are provided.

Description

SYNTHESIS AND COMPOSITION OF RAPAFUCIN LIBRARIES
RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/291,437, filed on February 4, 2016, which is hereby incorporated herein by reference in its entirety.
GRANT INFORMATION
[0002] This invention was made with government support under National Institutes of Health grant DP1CA174428. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
[0003] The invention relates generally to hybrid cyclic molecules, and more specifically to hybrid cyclic libraries based on the immunophilin ligand family of natural products FK506 and rapamycyin.
BACKGROUND INFORMATION
[0004] The macrocyclic natural products FK506 and rapamycin are approved immunosuppressive drugs with important biological activities. Both have been shown to inhibit T cell activation, albeit with distinct mechanisms. In addition, rapamycin has been shown to have strong anti-proliferative activity. FK506 and rapamycin share an extraordinary mode of action; they act by recruiting an abundant and ubiquitously expressed cellular protein, the prolyl cis-trans isomerase FKBP, and the binary complexes subsequently bind to and allosterically inhibit their target proteins calcineurin and mTOR, respectively. Structurally, FK506 and rapamycin share a similar FKBP-binding domain but differ in their effector domains. In FK506 and rapamycin, nature has taught us that switching the effector domain of FK506 to that in rapamycin, it is possible to change the targets from calcineurin to mTOR. The generation of a rapafucin library of macrocyles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.
[0005] With the completion of the sequencing and annotation of the human genome, a complete catalog of all human proteins encoded in the genome is now available. The functions of a majority of these proteins, however, remain unknown. One way to elucidate the functions of these proteins is to find small molecule ligands that specifically bind to the proteins of interest and perturb their biochemical and cellular functions. Thus, a major challenge for chemical biologists today is to discover new small molecule probes for new proteins to facilitate the elucidation of their functions. The recent advance in the development of protein chips has offered an exciting new opportunity to simultaneously screen chemical libraries against nearly the entire human proteome. A single chip, in the form of a glass slide, is sufficient to display an entire proteome in duplicate arrays. Recently, a protein chip with 17,000 human proteins displayed on a single slide has been produced. A major advantage of using human protein chips for screening is that the entire displayed proteome can be interrogated at once in a small volume of assay buffer (<3 mL). Screening of human protein chips, however, is not yet feasible with most, if not all, existing chemical libraries due to the lack of a universal readout for detecting the binding of a ligand to a protein on these chips. While it is possible to add artificial tags to individual compounds in a synthetic library, often the added tags themselves interfere with the activity of ligands. Thus, there remains a need for new compounds and methods for screening chemical libraries against the human proteome.
SUMMARY OF THE INVENTION
[0006] One embodiment of the present invention is to provide a compound of the following structure:
Figure imgf000003_0001
. R1 and R3 can independently be any of the following compounds:
Figure imgf000003_0002
R2 and R4 can independently be any of the following compounds:
Figure imgf000004_0001
[0007] Another embodiment of the present invention is to provide a compound of the following structure:
Figure imgf000004_0002
R1, R2, R3 and R4 are selected from the same groupings of compounds listed above.
[0008] Another embodiment of the present invention is to provide a compound that includes A15-34-2, A15-39-1, A15-39-2, A15-39-4, A15-39-6, A15-39-8, A15-39-15, A15- 40-2, A15-40-4, A15-40-15, E15-32-2, E15-33-1, E15-33-2, E15-34-1, E15-34-2, E15-39-1, E15-39-2, E15-39-5, E15-40-2, E15-40-4, E15-S-19, E15-S-21, and E15-S-22.
[0009] Another embodiment of the present invention is to provide synthetic methods as outlined in the“Detailed Description of the Invention” for producing a Rapafucin library.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Figure 1. Number of compounds in library. DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
[0011] Scheme 1- Synthetic scheme for Rapafucin molecules containing amide mFKBD
Figure imgf000005_0001
[0012] R1 and R3 in Scheme 1 are amino acids selected from the following group of amino acids:
Figure imgf000005_0002
[0013] R2 and R4 in Scheme 1 are amino acids selected from the following group of amino acids:
Figure imgf000006_0001
[0014] The synthesis of the amide mFKBD in Scheme 1 is as follows:
Figure imgf000006_0002
Figure imgf000007_0001
[0015] The synthesis of the ether mFKBD in Scheme 1 is as follows:
Figure imgf000007_0002
[0016] The general formula for a Rapafucin with an amide mFKBD is represented by “A”.
Figure imgf000008_0001
[0017] The general formula for a Rapafucin with an ether mFKBD is represented by“E”.
Figure imgf000008_0002
[0018] Specific Examples of“A” and“E” as well as their properties are listed in Table 1.
Figure imgf000009_0001
Table 1 [0019] Approximately, 45,000 compounds were obtained as part of the Rapafucin library (Fig.1).
[0020] Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.
REFERENCES
The following reference is relied upon and incorporated herein in its entirety. 1. US 2014/0073581.

Claims

CLAIMS What is claimed is:
1. A compound of Formula I:
Figure imgf000011_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Figure imgf000011_0002
or
Figure imgf000012_0001
wherein R1, R2, R3, R4, and R5 are each independently selected from hydrogen, hydroxyl, alkoxy,
Figure imgf000012_0002
cyano, alkylthio, amino, and alkylamino, is a resin;
wherein one, two, three, or four of A1, A2, A3, A4, and A5 is N or P with the remaining being CH;
wherein one, two, three, or four of B1, B2, B3 and B4 is O, N, or S with the remaining being CH or CH2 as appropriate;
wherein is a single or double bond;
6;
Figure imgf000012_0003
W is O, CH, CH2, CR9, or C R10R11;
L1 and L2 are each independently a direct bond, substituted or unsubstituted -(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)(C1- C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)O(C1-C6)alkyl-, substituted or unsubstituted - (CH2)nOC(O)(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)NH(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted -(C2- C6)alkenyl-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nC(O)(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nNH(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nC(O)(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted -(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkynyl-, substituted or unsubstituted - (CH2)nOC(O)(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nS(C2- C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl-, substituted or unsubstituted -(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl- NR18-, substituted or unsubstituted - (CH2)nC(O)O(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl- NR18-, substituted or unsubstituted - (CH2)nC(O)NH(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl- NR18-, substituted or unsubstituted -(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nC(O)O(C2- C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkenyl- NR18-, substituted or unsubstituted - (CH2)nC(O)NH(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl- NR18- , substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl- NR18- , substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl- NR18-, substituted or unsubstituted - (CH2)nC(O)O(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nS(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)O(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)NH(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)O(C2- C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkenyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)NH(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl- C(O)- , substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl- C(O)- , substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)O(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nS(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl- C(O)-, -O-, -NH-, -S-, - S(O)-, -SO2-, -Si-, and -B-, wherein each alkyl, alkenyl, and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, hydroxyl, sulfhydryl, halogen, carboxyl, oxo, cyano, nitro, or trifluoromethyl;
L3 is a direct bond, substituted or unsubstituted -(C1-C6)alkyl-, substituted or unsubstituted - (CH2)nO(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)O(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nOC(O)(C1- C6)alkyl-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl-, substituted or unsubstituted - (CH2)nC(O)NH(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted -(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nC(O)(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nNH(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nC(O)(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted -(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkynyl-, substituted or unsubstituted - (CH2)nOC(O)(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nS(C2- C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl-, substituted or unsubstituted -(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl- NR18-, substituted or unsubstituted - (CH2)nC(O)O(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl- NR18-, substituted or unsubstituted - (CH2)nC(O)NH(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl- NR18-, substituted or unsubstituted -(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nC(O)O(C2- C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkenyl- NR18-, substituted or unsubstituted - (CH2)nC(O)NH(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl- NR18- , substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkenyl- NR18-, substituted or unsubstituted -(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl- NR18- , substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl- NR18-, substituted or unsubstituted - (CH2)nC(O)O(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nS(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl- NR18-, substituted or unsubstituted -(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)O(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)NH(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1-C6)alkyl- C(O)-, substituted or unsubstituted -(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nO(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)O(C2- C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkenyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)NH(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl- C(O)- , substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkenyl- C(O)-, substituted or unsubstituted -(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl- C(O)- , substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkynyl- C(O)-, substituted or unsubstituted - (CH2)nC(O)O(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nOC(O)(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nNH(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nS(C2-C6)alkynyl- C(O)-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl- C(O)-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, hydroxyl, sulfhydryl, halogen, carboxyl, oxo, cyano, nitro, or trifluoromethyl;
each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
R6 is hyrdrogen or alkyl;
R7 and R8 are each independently selected from hydrogen, hydroxy, alkyl, alkoxy, cyano, alkylthio, amino, and alkylamino, and OPG, wherein OPG is a protecting group;
R9, R10, and R11 are each independently selected from hydrogen, hydroxy, alkyl, alkoxy, cyano, alkylthio, amino, and alkylamino, and OPG, wherein OPG is a protecting group;
wherein the Effector Domain has Formula II:
Figure imgf000016_0001
(II) wherein:
R12, R14, R16, and R18 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5.
R13, R15, and R17 are each independently the sidechains of naturally occurring amino acids and their modified forms including but are not limited to D-amino acid configuration, or hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, substituted or unsubstituted (CH2)n-aryl, substituted or unsubstituted (CH2)n-heteroaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR19, (CH2)nC(O)R19, (CH2)nC(O)OR19, (CH2)nOC(O)R19, (CH2)nNR20R21, (CH2)nC(O)NR20R21, (CH2)nNR22C(O)R19, (CH2)nNR22C(O)OR19, (CH2)nNR22C(O)NR20R21, (CH2)nSR19, (CH2)nS(O)jNR20R21, (CH2)nNR22S(O)jR19, or - (CH2)nNR22S(O)jNR20R21;
R12 and R13, R14 and R15, R16 and R17 can be convalently connected to form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycle.
each k is independently an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
each j is independently an integer selected from 0, 1, and 2;
R19, R20, R21, and R22 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or R19 and R22 are as described above, and R20 and R21, together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl,
wherein each of the above groups listed for R13, R15, and R17 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR19, (CH2)nC(O)R19, (CH2)nC(O)OR19, (CH2)nOC(O)R19, (CH2)nNR20R21, (CH2)nC(O)NR20R21, (CH2)nNR22C(O)R19, (CH2)nNR22C(O)OR19, (CH2)nNR22C(O)NR20R21, (CH2)nSR19, (CH2)nS(O)jNR20R21, (CH2)nNR22S(O)jR19, or -(CH2)nNR22S(O)jNR20R21;
or wherein the Effector Domain has Formula III:
Figure imgf000017_0001
wherein:
each k is independently an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
R23 is a hydrogen or alkyl;
X3 is substituted or unsubstituted -(C1-C30)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH2, CH-OH, C(O);
or wherein the Effector Domain has Formula IV:
Figure imgf000018_0001
wherein:
X4 is substituted or unsubstituted -(C1-C30)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH2, CH-OH, C(O).
Or wherein the Effector Domain has Formula V:
wherein:
Figure imgf000018_0004
R24 and R25 are each a hydrogen or alkyl;
X5 is substituted or unsubstituted -(C1-C30)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH2, CH-OH, C(O).
Or wherein the Effector Domain has Formula VI:
Figure imgf000018_0002
wherein: X6 is substituted or unsubstituted -(C1-C30)alkyl-, alkenyl-, alkynyl- with each carbon individually assuming one of the following redox states: CH2, CH-OH, C(O).
2. The compound of formula I of claim 1, wherein
Figure imgf000018_0003
y
3. The compound of formula I of claim 1, wherein
R is as defined in claim 1 but not
Figure imgf000019_0001
wherein R3 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or
Figure imgf000019_0002
a resin; wherein R2 is hydrogen, hydroxyl, or alkoxy; and
wherein R1, R4, and R5 are each independently hydrogen or no substituent as dictated by chemical bonding;
wherein is a single or double bond.
4. The compound of formula I of claim 1, wherein
L1 and L2 and the Effector Domain are as defined in claim 1
but L1 and L2 not each independently direct bond, substituted or unsubstituted -(C1- C6)alkyl-, substituted or unsubstituted -(CH2)nO(C1-C6)alkyl-, substituted or unsubstituted - (CH2)nC(O)-, substituted or unsubstituted -(CH2)nC(O)(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)O(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nNH(C1- C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)NH(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C1- C6)alkyl-, substituted or unsubstituted -(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nO(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nNH(C1-C6)alkenyl-, substituted or unsubstituted -(CH2)nC(O)NH(C2-C6)alkenyl-, substituted or unsubstituted -(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted - (CH2)nC(O)(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted -(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nO(C2-C6)alkynyl-, substituted or unsubstituted - (CH2)nC(O)(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)O(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nNH(C1-C6)alkynyl-, substituted or unsubstituted - (CH2)nC(O)NH(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nS(C2-C6)alkynyl-, substituted or unsubstituted -(CH2)nC(O)(CH2)nS(C2-C6)alkynyl-, wherein each alkyl, alkenyl, and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;
and the Effector Domain is a compound of Formula VIII
Figure imgf000020_0001
wherein
R12, R14, R14’, R16, and R27 are not each independently hydrogen or alkyl and
R13, R14, R14’, and R16 are not each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR19, (CH2)nC(O)R19, (CH2)nC(O)OR19, (CH2)nOC(O)R19, (CH2)nNR20R21, (CH2)nC(O)NR20R21, (CH2)nNR22C(O)R19, (CH2)nNR22C(O)OR19, (CH2)nNR22C(O)NR20R21, (CH2)nS(O)jNR20R21, (CH2)nNR22S(O)jR19, or -(CH2)nNR22S(O)jNR20R21;
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
j is an integer selected from 0, 1, and 2;
R19, R20, R21, and R22 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or R19 and R22 are as described above, and R20 and R21, together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl,
wherein each of the above groups listed for R13, R15, and R17 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR19, (CH2)nC(O)R19, (CH2)nC(O)OR19, (CH2)nOC(O)R19, (CH2)nNR20R21, (CH2)nC(O)NR20R21, (CH2)nNR22C(O)R19, (CH2)nNR22C(O)OR19, (CH2)nNR22C(O)NR20R21, (CH2)nSR19, (CH2)nS(O)jNR20R21, (CH2)nNR22S(O)jR19, or -(CH2)nNR22S(O)jNR20R21.
5. The compound of formula I of claim 1, wherein
L3 is–CH2CH2– ;
R is
Figure imgf000021_0001
R1 , R4, R5 and R6 are each hydrogen;
R2 and R3 are each methoxy;
m = 0;
Figure imgf000021_0002
X2 is O or NR6C(O)
L1 is–CH2-C(O)- or -(CH2)2C(O)-;
Figure imgf000021_0003
L2 is–OCO-CH=CH-(CH2)2N(Me)-; The compound of claim 5, wherein the effector domain of formula II has formula VII
Figure imgf000021_0004
Wherein R12, R14, R14’, and R16 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5.
R13, R15, R15’ and R17 are each independently the sidechains of naturally occurring amino acids and their modified forms including but are not limited to D-amino acid configuration, or hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, substituted or unsubstituted (CH2)n-aryl, substituted or unsubstituted (CH2)n-heteroaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR19, (CH2)nC(O)R19, (CH2)nC(O)OR19, (CH2)nOC(O)R19, (CH2)nNR20R21, (CH2)nC(O)NR20R21, (CH2)nNR22C(O)R19, (CH2)nNR22C(O)OR19, (CH2)nNR22C(O)NR20R21, (CH2)nSR19, (CH2)nS(O)jNR20R21, (CH2)nNR22S(O)jR19, or - (CH2)nNR22S(O)jNR20R21.
R12 and R13, R14 and R15, R14’ and R15’, R16 and R17 can be covalently connected to form a substituted or unsubstituted 5-,
6-, or 7-membered heterocycle.
7. The compound of claim 5, wherein the effector domain of formula II has formula VIII -AA1-AA2-AA3-AA4- (VIII)
wherein AA1, AA2, AA3 and AA4 are each independently selected from:
Figure imgf000023_0001
Figure imgf000024_0001
8. The compound of claim 5, wherein
X2 is O and L1 is–CH2-C(O)- .
9. The compound of claim 5, wherein
X2 is NR6C(O) and L1 is -(CH2)2C(O)- .
10. A method for synthesizing a compound or libraries of compounds selected from those described in claim 1 comprising the steps disclosed in the“Detailed Description of the Invention”.
11. A method of using a hybrid cyclic library based on the immunophilin ligand family of natural products FK506 and rapamycin, to screen for compounds for treating cancer.
12. A method of using a hybrid cyclic library based on the immunophilin ligand family of natural products FK506 and rapamycin, to screen for compounds for treating autoimmune disease.
PCT/US2017/016481 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries WO2017136708A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA3013589A CA3013589A1 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
EP17748264.3A EP3411413A4 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
CN201780010182.2A CN108713028B (en) 2016-02-04 2017-02-03 Synthesis and compositions of rapafucin libraries
JP2018540102A JP6891183B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of the rapafcin library
MX2018009405A MX2018009405A (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries.
AU2017214550A AU2017214550B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of Rapafucin libraries
US16/074,017 US10662220B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
US16/590,087 US11066416B2 (en) 2016-02-04 2019-10-01 Rapafucin derivative compounds and methods of use thereof
US17/332,331 US11945827B2 (en) 2016-02-04 2021-05-27 Rapafucin derivative compounds and methods of use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662291437P 2016-02-04 2016-02-04
US62/291,437 2016-02-04

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/074,017 A-371-Of-International US10662220B2 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries
US16/590,087 Continuation-In-Part US11066416B2 (en) 2016-02-04 2019-10-01 Rapafucin derivative compounds and methods of use thereof

Publications (1)

Publication Number Publication Date
WO2017136708A1 true WO2017136708A1 (en) 2017-08-10

Family

ID=59501078

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/016481 WO2017136708A1 (en) 2016-02-04 2017-02-03 Synthesis and composition of rapafucin libraries

Country Status (8)

Country Link
US (1) US10662220B2 (en)
EP (1) EP3411413A4 (en)
JP (2) JP6891183B2 (en)
CN (1) CN108713028B (en)
AU (1) AU2017214550B2 (en)
CA (1) CA3013589A1 (en)
MX (1) MX2018009405A (en)
WO (1) WO2017136708A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018225864A1 (en) * 2017-06-09 2018-12-13 中外製薬株式会社 Cyclic peptide compound having high membrane permeability, and library containing same
EP3411032A4 (en) * 2016-02-04 2019-08-14 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
WO2021067439A1 (en) 2019-10-01 2021-04-08 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11066416B2 (en) 2016-02-04 2021-07-20 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11708391B2 (en) 2016-02-04 2023-07-25 The Johns Hopkins University Rapaglutins, novel inhibitors of GLUT and use thereof
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3411413A4 (en) * 2016-02-04 2019-09-18 The Johns Hopkins University Synthesis and composition of rapafucin libraries

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
US20020052410A1 (en) * 1995-06-07 2002-05-02 Steiner Joseph P. Rotamase enzyme activity inhibitors
US6984635B1 (en) * 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
US20080306098A1 (en) * 2006-11-06 2008-12-11 Mutz Mitchell W Pharmacokinetics of protease inhibitors and other drugs
US20090253732A1 (en) * 2004-08-11 2009-10-08 Biotica Technology Limited Production Of Polyketides And Other Natural Products
WO2010004304A1 (en) * 2008-06-17 2010-01-14 Biotica Technology Limited Novel compounds and methods for their production
US20140073581A1 (en) 2010-11-30 2014-03-13 The Johns Hopkins University Hybrid Cyclic Libraries and Screens Thereof
WO2014201405A1 (en) * 2013-06-14 2014-12-18 The Board Of Regents Of The University Of Texas System Novel allosteric inhibitors of proteasome and methods of use thereof
US20150018340A1 (en) * 2011-12-22 2015-01-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Pipecolate-diketoamides for treatment of psychiatric disorders

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5798355A (en) * 1995-06-07 1998-08-25 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US5696135A (en) * 1995-06-07 1997-12-09 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth
CN1187127A (en) * 1995-06-07 1998-07-08 吉尔福特药品有限公司 Inhibitors of Rotamase enzyme activity
AU766513B2 (en) * 1998-02-13 2003-10-16 Board Of Trustees Of The Leland Stanford Junior University Novel dimerizing agents, their production and use
EP3411413A4 (en) * 2016-02-04 2019-09-18 The Johns Hopkins University Synthesis and composition of rapafucin libraries

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5527907A (en) * 1993-11-19 1996-06-18 Abbott Laboratories Macrolide immunomodulators
US20020052410A1 (en) * 1995-06-07 2002-05-02 Steiner Joseph P. Rotamase enzyme activity inhibitors
US6984635B1 (en) * 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
US20090253732A1 (en) * 2004-08-11 2009-10-08 Biotica Technology Limited Production Of Polyketides And Other Natural Products
US20080306098A1 (en) * 2006-11-06 2008-12-11 Mutz Mitchell W Pharmacokinetics of protease inhibitors and other drugs
WO2010004304A1 (en) * 2008-06-17 2010-01-14 Biotica Technology Limited Novel compounds and methods for their production
US20140073581A1 (en) 2010-11-30 2014-03-13 The Johns Hopkins University Hybrid Cyclic Libraries and Screens Thereof
US20150018340A1 (en) * 2011-12-22 2015-01-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Pipecolate-diketoamides for treatment of psychiatric disorders
WO2014201405A1 (en) * 2013-06-14 2014-12-18 The Board Of Regents Of The University Of Texas System Novel allosteric inhibitors of proteasome and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3411413A4

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11891457B2 (en) 2011-12-28 2024-02-06 Chugai Seiyaku Kabushiki Kaisha Peptide-compound cyclization method
EP3411032A4 (en) * 2016-02-04 2019-08-14 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
US10774110B2 (en) 2016-02-04 2020-09-15 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
EP3782636A1 (en) * 2016-02-04 2021-02-24 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
US11066416B2 (en) 2016-02-04 2021-07-20 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
US11555054B2 (en) 2016-02-04 2023-01-17 The Johns Hopkins University Rapadocins, inhibitors of equilibrative nucleoside transporter 1 and uses thereof
US11708391B2 (en) 2016-02-04 2023-07-25 The Johns Hopkins University Rapaglutins, novel inhibitors of GLUT and use thereof
US11945827B2 (en) 2016-02-04 2024-04-02 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
WO2018225864A1 (en) * 2017-06-09 2018-12-13 中外製薬株式会社 Cyclic peptide compound having high membrane permeability, and library containing same
WO2021067439A1 (en) 2019-10-01 2021-04-08 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof
EP4037702A4 (en) * 2019-10-01 2023-10-18 The Johns Hopkins University Rapafucin derivative compounds and methods of use thereof

Also Published As

Publication number Publication date
AU2017214550B2 (en) 2024-03-07
MX2018009405A (en) 2018-11-09
EP3411413A1 (en) 2018-12-12
CN108713028A (en) 2018-10-26
CA3013589A1 (en) 2017-08-10
EP3411413A4 (en) 2019-09-18
CN108713028B (en) 2021-12-28
US20190092808A1 (en) 2019-03-28
JP6891183B2 (en) 2021-06-18
AU2017214550A1 (en) 2018-08-16
US10662220B2 (en) 2020-05-26
JP7158532B2 (en) 2022-10-21
JP2019510738A (en) 2019-04-18
JP2021138726A (en) 2021-09-16

Similar Documents

Publication Publication Date Title
AU2017214550B2 (en) Synthesis and composition of Rapafucin libraries
US10954273B2 (en) Hybrid cyclic libraries and screens thereof
Furukawa et al. Passive membrane permeability in cyclic peptomer scaffolds is robust to extensive variation in side chain functionality and backbone geometry
Kobayashi et al. Celogentins A− C, New Antimitotic Bicyclic Peptides from the Seeds of Celosia a rgentea
Wu et al. Creating diverse target-binding surfaces on FKBP12: synthesis and evaluation of a rapamycin analogue library
Whitty et al. Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery
Stern et al. A low-temperature EPR study of partially purified, soluble ferric cytochromes P-450 and P-448 from rat liver microsomes
CA2565872C (en) T-cell death-inducing epitopes
Xie et al. Discovery of quorum quenchers targeting the membrane-embedded sensor domain of the Staphylococcus aureus receptor histidine kinase, AgrC
Ciminiello et al. Spirolide toxin profile of Adriatic Alexandrium ostenfeldii cultures and structure elucidation of 27-hydroxy-13, 19-didesmethyl spirolide C
Wennemers et al. Flexible but with a Defined Turn—Influence of the Template on the Binding Properties of Two‐Armed Receptors
Kwon et al. Cyclopeptides from the Sponge Stylissa flabelliformis
Skalniak et al. A fluorinated indole‐based MDM 2 antagonist selectively inhibits the growth of p53wt osteosarcoma cells
Zhou et al. Cyclopeptides from the mushroom pathogen fungus Cladobotryum varium
JP2023139104A (en) Binding competitors for use in macrophilin-binding pharmaceutical assays and methods of use thereof
JP4496168B2 (en) Method for removing non-specific substances
Xu et al. Short divalent ethacrynic amides as pro-inhibitors of glutathione S-transferase isozyme Mu and potent sensitisers of cisplatin-resistant ovarian cancers
Atkinson et al. Development of small cyclic peptides targeting the CK2α/β interface
Sobieściak et al. Double selective synthetic approach to the N-functionalized 1, 4, 7-triazacyclononane derivatives: Chelating compounds for controllable protein orientation
CN114008457A (en) Sandwich immunoassay reagents using particle-enhanced agglutination assays and methods of making and using same
Kong et al. Isolation and structure of homotemsirolimuses A, B, and C
Tuin et al. Synthesis and biological evaluation of novel gramicidin s analogues
CDI ROSE MERCADANTE SEMINAR SERIES
Baumann et al. NMR study on 9‐S and 9‐R oxirane derivatives of ascomycin
Früh et al. Target immobilized NMR screening: Validation and extension to membrane proteins

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17748264

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2018540102

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2018/009405

Country of ref document: MX

Ref document number: 3013589

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017214550

Country of ref document: AU

Date of ref document: 20170203

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2017748264

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017748264

Country of ref document: EP

Effective date: 20180904